This is a resubmission of an application in response to PA-07-279 Bioengineering Research Grant (R01), which supports basic and applied multi-disciplinary research that addresses important biological, bioengineering or medical research problems using an integrative, systems approach. Targeted Problem: Artery tortuosity occurs when normally straight arteries take an abnormal curved and tortuous path. Tortuous arteries are common angiographic findings in humans and occur in a multitude of arteries, from aorta to capillary, cerebral to coronary arteries, and carotid to femoral arteries. Tortuous corkscrew collateral arteries frequently occur in patients with occlusive peripheral vascular disease. Clinical studies suggest that high blood pressure, aging, atherosclerosis, and rare genetic mutations are each associated with higher risks of artery tortuosity, and tortuosity is believed to precipitate the development of atherosclerosis and hypertension. However, the underlying etiology and biomechanical mechanism of artery tortuosity remain unclear. The objective of this study is to determine the biomechanical mechanisms of artery tortuosity by investigating the interactions between vascular hemodynamics, buckling, and wall remodeling. Our central hypothesis is that elevated pulsatile pressure or weakened arterial wall initiates arterial buckling which then stimulates asymmetric wall remodeling that exacerbate buckling and gradually leads to arterial tortuosity. The two specific aims are to determine what types of blood flow, mechanical stress, and wall property changes initiate artery buckling and how buckling affects arterial blood flow and wall stress, as well as the associated adaptation of the arterial wall that leads to tortuosity. Methods: Artery buckling will be examined using biomechanics-based modeling and experimental tests under pulsatile flow conditions. The effect of wall matrix degradation on artery buckling will be evaluated in porcine carotid arteries using elastase and collagenase treatments to degrade specific matrix components. The blood flow, wall stress, and arterial wall remodeling in buckled arteries will be examined using a unique ex vivo organ culture system combined with computational modeling. Outcomes: This study will establish mathematical and experimental models of artery dynamic buckling to determine the mechanisms that define the relationship among mechanical stress, artery buckling, and wall remodeling. Benefits: The new knowledge obtained from these studies will provide guidance in developing new techniques for the prevention and treatment artery tortuosity by targeting the mechanical factors and broaden our knowledge of vascular biomechanics.